A major objective of the proposed program is to further clarify the pathophysiology of chronic renal disease. Studies are designed to identify systemic and local factors of pivotal importance to renal disease and adaption as well as to elucidate the mechanism by which these factors modulate target cell physiology. Each project is focused on a different target cell with an essential role in the pathophysiology of renal disease and adaptation or order to develop an integrated picture of kidney function. Studies will be performed in normal animals or animals with experimentally induced renal disease or mineral or acid-base disorders and experiments will be conducted in the animals in vivo (clearances, response to hormones etc.) or in tissues or segments of tissues studied in vitro, such as glomeruli, brush border or basolateral membranes from renal tubules. In other project fundamental information which is applicable to the chronic renal disease state will be derived from in vitro experiments. Tissue cultures of different types of cells will be utilized in some of the projects. The four projects and two cores will examine: the modulation of endothelial cell function by clacitropic hormones (Project 1); Project 2 focusses on the cellular mechanism by which 1,25(OH)2D3, is regulated in renal disease and the mechanism by which it modulates parathyroid tissue and PTH secretion. Project 3 will examine the role of arginine and nitric oxide in the pathophysiology of obstructive nephropathy, including its effects on macrophage infiltration. Alterations in the physiology of the H+ATPase in disease states and the underlying mechanisms responsible for these alterations will be explored in Project 4. The studies proposed in these four projects represent logical extensions of work currently in progress in the different laboratories. Core A (administrative) and Core B (hybridomas, recombinant DNA probes) will provide the support needed by the different investigators participating in this Program Project.